Transcript LH and steroid hormone secretion in controlled ovarian

The optimal choice of
gonadotrophin in GnRH
antagonist protocols
Prof Dr P Devroey
Recent trends in ART practice
• Increasing use of GnRH antagonists with lower doses
of gonadotrophin
• Increasing use of ICSI over the last decade
• Increasing use of single embryo transfer
• Increasing use of embryo culture to blastocyst stage
• Increasing use of vitrification instead of slow-freezing
Why the MEGASET trial?
• MEGASET compares HP-hMG (MENOPUR®) with
rFSH (PUREGON®) in a setting that addresses
these recent trends in ART practice
• Randomised, assessor-blind, parallel groups, multicentre trial to demonstrate non-inferiority of HPhMG compared to rFSH with respect to ongoing
pregnancy rates
Participating clinics
25 clinics in 7 countries
Key design features
•
•
•
•
•
•
•
•
•
•
•
Women 18–34 years
BMI 18–24.9 kg/m2
GnRH antagonist
No programming
150 IU starting dose
ICSI
Blastocyst culture
Single blastocyst transfer on Day 5
2 weeks luteal support
Vitrification
Replacement of a single warmed blastocyst in a natural cycle
Trial design
GnRH antagonist
0.25 mg
rhCG
250 μg
HP-hMG or rFSH
150 IU x 5 days
Adjustment by
75 IU;
minimum 4
days on dose
1
6
Oocyte/embryo/
blastocyst
evaluation
β-hCG
OR
3 follicles ≥ 17mm
Progesterone
3x200 mg
OR
+5
13-15
days
after ET
Clin. P
Ong. P
5-6
10-11
weeks weeks
after ET after ET
ET
1 blastocyst
Post-trial follow-up
Ongoing
pregnancy
No ongoing
pregnancy
FER
1 blastocyst
natural cycle
Ongoing
pregnancy
Pregnancy outcome
and neonatal health follow-up
No ongoing
pregnancy
Pregnancy outcome and
neonatal health follow-up
Investigations: All patients
• Endocrine profile
• Follicular development
• Ovarian response
• Endometrial profile
• Pregnancy rates
• Cumulus mass appearance
• Oocyte maturation, fertilisation
• Embryo quality
• Blastocyst quality
Additional investigations: Subgroups of
patients
• Early-mid follicular phase endocrine profile
• Intrafollicular endocrine profile
• Uterine contractility
• Modelling of follicles
• Modelling of endometrium
• Gene expression in cumulus cells
(mechanical dissection and enzymatic denudation)
METHODOLOGY
Primary endpoint of the study
• Ongoing pregnancy rates beyond 10–11
weeks after ET in a fresh cycle
Power calculation
•
Estimated ongoing pregnancy rate of 30% was
derived from previous studies on single
blastocyst transfer
•
Non-inferiority margin was set at –10% (absolute)
•
At least 660 cycles was required to achieve a
study power of 80%
Analysis of data
• Modified Intention-to-treat (ITT) analysis
– All subjects who have been randomised and
exposed to at least one dose of investigational
medicinal product were analysed according to
the actual treatment
• Per protocol analysis
– All subjects from the modified ITT, except
those who are excluded because of a major
protocol deviation were analysed
EMBRYO ASSESSMENT
Embryo morphology assessment and grading
• Local embryologists only; no central evaluation
• Interobserver agreement and intraobserver
reproducibility were validated in the MERiT trial
showing good–excellent agreement on overall
embryo morphology assessment and grading1
• Embryos were graded according to the
Gardner and Schoolcraft classification system2
1. Arce et al. Hum Reprod 2006; 21: 2141–2148
2. Gardner and Schoolcraft. In: Towards reproductive certainty (Eds Jansen & Mortimer). The plenary proceedings of the 11 th
world congress on in vitro fertilization and human reproductive genetics. The Parthenon Publishing Group. 1999. Pp 378–388
Endometrial assessment
• Thickness
• Triple-layer structure
• Echogenicity pattern
SUBJECT DISPOSITION
Consort diagram
Screened (N=810)
Randomised and exposed (n=749)
HP-hMG (ITT; N=374)
rFSH (ITT; N=375)
Oocyte retrieval N=362
Oocyte retrieval N=362
Embryo transfer N=305
Embryo transfer N=316
β-hCG visit N=305
β-hCG visit N=316
Ongoing pregnancy
visit N=116
Ongoing pregnancy
visit N=107
BASELINE PARAMETERS
Demographics and treatment history
– ITT population
Primary reason of infertility
Unexplained
38%
Mild male
factor 62%
HP-hMG
Unexplained
40%
rFSH
Mild male
factor 60%
Demographics
HP-hMG
(N=374)
rFSH
(N=375)
Age (years)
30.8 ± 2.8
30.4 ± 2.6
Weight (kg)
60.6 ± 6.8
59.9 ± 7.0
BMI (kg/m2)
22.1 ± 1.9
21.9 ± 2.0
Duration of infertility (yrs)
3.2 ± 1.8
3.1 ± 1.7
Treatment history
HP-hMG
(N=374)
rFSH
(N=375)
1st or 2nd COS cycle ever
95%
95%
Previous IUI cycles, total
49%
52%
Previous IUI cycles, with
gonadotrophins
29%
31%
ENDOCRINE PROFILE
Endocrine Profile – Stimulation day 1
Endocrine profile
HP-hMG
(N=374)
rFSH
(N=375)
FSH (IU/L)
7.5 ± 2.3
7.4 ± 2.4
LH (IU/L)
6.2 ± 2.3
6.2 ± 2.2
Estradiol (pmol/L)
180 ± 106
177 ± 100
Progesterone (nmol/L)
2.2 ± 1.1
2.2 ± 1.1
Total testosterone (nmol/L)
1.6 ± 0.8
1.7 ± 0.8
Inhibin B (ng/L)
87 ± 40
85 ± 35
AMH (pmol/L)
27 ± 19
27 ± 20
Data are mean ± SD
ITT-population
Endocrine profile – stimulation day 6
HP-hMG
(N=374)
rFSH
(N=375)
p value
LH (IU/L)
4.9 ± 5.0
5.5 ± 6.0
0.558
hCG (IU/L)
1.7 ± 0.6
-
-
2626 ± 1405
2973 ± 1702
0.003
Progesterone (nmol/L)
2.2 ± 1.9
2.8 ± 10.8
0.025
Total testosterone (nmol/L)
1.9 ± 0.9
1.9 ± 0.9
0.169
Inhibin B (ng/L)
604 ± 324
722 ± 424
<0.001
Estradiol (pmol/L)
Data are mean ± SD
ITT-population
Early-mid follicular phase: LH
LH
Change over time
IU/L
6
5
HP-hMG
rFSH
4
3
2
1
HP-hMG
(N=49)
rFSH
(N=50)
Day 1 →
Day 2
-22%
-26%
Day 2 →
Day 4
-42%
-47%
Day 1 →
Day 4
-60%
-61%
Day 4 →
Day 6
10%
24%
Day 1 →
Day 6
-50%
-57%
0
Day 1
Day 2
Day 4
Median values
Day 6
ITT-population / early-mid follicular phase
sub-group
Endocrine profile – last stimulation day
HP-hMG
(N=374)
rFSH
(N=375)
p value
LH (IU/L)
2.8 ± 2.8
2.1 ± 1.6
<0.001
hCG (IU/L)
2.1 ± 0.8
-
-
8797 ± 6030
7022 ± 4945
<0.001
Progesterone (nmol/L)
3.1 ± 3.4
3.1 ± 3.3
0.630
Total testosterone (nmol/L)
2.5 ± 1.2
2.1 ± 1.0
<0.001
Estradiol (pmol/L)
Mean ± SD
ITT-population
Premature luteinization
Premature luteinization*
- LH ≥ 10 IU/L
- Progesterone ≥ 1 ng/mL (3.18 nmol/L)
HP-hMG
(N=374)
rFSH
(N=375)
5.9%
6.1%
ITT-population
*Both
LH and progesterone criteria to be met at the same visit
(ie. Stimulation Day 6 or Last Stimulation Day)
TREATMENT EFFICIENCY
Follicular development
Stimulation Day 6
HP-hMG
rFSH
Last Stimulation Day
p<0.05
HP-hMG
rFSH
p<0.05
Mean data
ITT-population
Oocytes
Protocol target
12
HP-hMG
(N=362)
Frequency (%) of subjects
10
8
Oocytes
retrieved
8 – 10
rFSH
(N=362)
9.1 ± 5.2 10.7 ± 5.8
p value
<0.001
6
4
HP-hMG
2
rFSH
0
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
Number of oocytes retrieved
ITT-population with oocyte retrieval
Exposure to gonadotrophins and
GnRH antagonist
Duration of gonadotrophin use
(days)
Total gonadotrophin dose (IU)
HP-hMG
(N=374)
rFSH
(N=375)
p value
8.8 ± 1.6
8.5 ± 1.3
0.077
1433 ± 371 1353 ± 296
0.009
Dose on Day 6
Decreased
1%
2%
Maintained
67%
73%
Increased
31%
25%
Percentages may not add to 100% due to rounding off
ITT-population
Endometrial pattern
– Day of embryo transfer
HP-hMG
(N=374)
rFSH
(N=375)
p value
11.1 ± 2.1
11.1 ± 2.2
-
53%
54%
0.873
Hypoechogenic
5%
6%
Isoechogenic
17%
17%
Hyperechogenic
73%
73%
Not possible to
evaluate
5%
4%
Endometrial thickness
(mm)
Triple-layer structure
Echogenic pattern
0.983
ITT-population
Availability of blastocysts on the day of ET
ITT-population
HP-hMG
rFSH
Subjects with blastocysts
82%
85%
Subjects with frozen blastocysts
55%
58%
Ongoing pregnancy rate per started cycle:
Primary endpoint
HP-hMG – rFSH
HP-hMG
rFSH
PP
30.0%
27.0%
3.0% (-3.8; 9.8)
ITT
28.9%
26.7%
2.2% (-4.2; 8.6)
Difference (95% CI)
Non-inferiority was demonstrated for both PP- and ITT-populations,
as the lower limit of the 95% confidence interval was above the preestablished non-inferiority margin of -10%
Pregnancy rates per started cycle
ITT-population
HP-hMG
rFSH
39
40
36
29
27
20
30
27
20
10
0
0
Clinical
Ongoing
pregnancy pregnancy
29
30
10
Positive
β-hCG
rFSH
32
29
30
40
36
31
Percentage (%)
HP-hMG
Percentage (%)
40
PP-population
Positive
β-hCG
Clinical
Ongoing
pregnancy pregnancy
Significantly lower ongoing pregnancy rate in rFSH
patients with higher progesterone levels at the end
of stimulation
p=0.95
30
29
30
p=<0.05
Progesterone ≤4nmol/L
29
Ongoing pregnancy
rate/cycle initiated (%)
Progesterone >4nmol/L
25
20
16
15
10
5
0
HP-hMG
rFSH
Blastocyst quality and ongoing pregnancy rate
Subjects according to their highest
blastocyst quality
100%
Ongoing pregnancy rate
by quality of transferred blastocyst
25%
80%
5 (hatching blastocyst)
Expansion and
hatching status
60%
4 (expanded blastocyst)
41%
4-5
46%
41%
1-3
13%
14%
ITT-population with embryo transfer
17%
2 (blastocoel filling ≥ 50%)
8%
0%
rFSH
(N=315)
3 (blastocoel filling 100%)
40%
20%
HP-hMG
(N=304)
9%
1 (early blastocoel)
Blastocyst expansion and
hatching status
ITT-population with blastocysts on Day 5
Pregnancy loss
HP-hMG
Abortion
N=8
rFSH
Biochemical
pregnancy
N=18
Ectopic
pregnancy
N=1
Abortion
N=7
Biochemical
pregnancy
N=14
Ectopic
pregnancy
N=1
Intrauterine pregnancy
without heart beat
N=10
37/374 = 10%
Intrauterine pregnancy
without heart beat
N=12
34/375 = 9%
Conclusions
• Primary endpoint of MEGASET study was achieved
• Largest multicentre, multinational RCT of HP-hMG vs
rFSH addressing new trends in ART in a robust, high
quality innovative trial with ICSI
• Demonstrates single blastocyst transfer is effective
with mild stimulation and lower number of oocytes
• Reinforces the importance of progesterone during the
late follicular phase
– Higher pregnancy rate with HP-hMG than rFSH when
progesterone >4 nmol/L